American Journal of Transplantation最新文献

Rapid diagnosis is pivotal in kidney disease for timely and precision therapy. Conventional microscopic and molecular assessments from biopsy tissues rely on extra sample processing, making same-day diagnosis impractical. Therefore, we introduce the biopsy transport medium (BTM), a byproduct of the biopsy tissue storage process that could serve as a source of biomarkers, accelerating the assessment workflow. Biopsies from tumor-free nephrectomy tissues were used to create mimicked BTM, allowing optimization of RNA extraction procedure. RNA yield and integrity were then systematically evaluated prior to downstream analyses. Subsequently, gene expression analysis was performed through multiple techniques: qPCR, RNA sequencing, and NanoString nCounter system. The results showed that storage time (the duration a biopsy is stored in BTM), ranging from 0.5 to 24 hours, did not significantly affect RNA quality and yield. The transcriptomic signals detected in biopsy tissues are largely recapitulated in the corresponding BTM samples. The differential gene expression analysis based on BTM identified rejection-associated profiles, which are aligned with Banff lesion scores. This study confirms BTM's ability to provide transcriptomic information relevant to the state of the kidney and supports BTM's potential for same-day molecular diagnosis, especially with tailored qPCR panels for rapid, targeted analysis.

Immunosuppressive drugs remain essential for preventing rejection but carry significant toxicities, underscoring the need for safer, physiology-based immunomodulators. Tributyrin, a prodrug of butyrate with improved systemic bioavailability, has emerged as a metabolically driven immune regulator. Here, we evaluated whether oral tributyrin promotes immune tolerance and improves graft outcomes in preclinical transplantation models. In minor-mismatch skin transplantation, tributyrin-treated recipients exhibited a significant, Treg-dependent prolongation of graft median survival time (33 [IQR 24.0-40.5] vs. 15.5 [IQR 12.0-18.0] days; p=0.0007). In a semi-allogeneic heart model, tributyrin similarly extended graft survival (52 [IQR 27.0-67.5] vs. 14.5 [IQR 12.25-22.0] days; p=0.0038). Oral tributyrin increased the frequency and activation of graft-infiltrating Tregs, marked by elevated IL-10, CTLA-4, LAG-3, and CD25, while reducing CD8⁺ T-cell infiltration and their IFN-γ and granzyme B production. Tributyrin treatment also modulated the intragraft innate compartment, reducing proinflammatory M1-macrophage signatures while promoting M2-macrophages with increased IL-10 expression. Systemically, splenocytes from treated recipients produced more IL-10 and displayed selective hyporesponsiveness to donor, but not to third-party antigens, consistent with antigen-specific regulation. Collectively, these findings demonstrate that oral tributyrin enhances regulatory pathways, suppresses alloreactive effector responses, and prolongs allograft survival, supporting its potential as a safe metabolic adjunct in transplantation.

Despite booster vaccinations, solid organ transplant (SOT) recipients develop suboptimal immunity and remain at risk of severe coronavirus disease 2019 (COVID-19). Chronic immunosuppression and repeated antigen exposure favor T cell exhaustion/senescence, potentially challenging the development of protective immunity. In a prospective multicenter study including 80 naïve SOT patients receiving 5 severe acute respiratory syndrome coronavirus 2 mRNA-based vaccine doses, exhausted/senescent T cell phenotypes were longitudinally profiled at distinct time points, and their impact on antigen-specific immune responses was assessed by antibodies, memory B cells, cytokine-producing T cells, and activation-induced markers on CD4 and CD8 T cells. We observed wide heterogeneity of vaccine-induced adaptive immunity across compartments. T cell exhaustion/senescence did not change after 3 vaccine doses. Notably, high percentages of CD57⁺, CD57⁺PD1⁺, programmed cell death protein 1 (PD1)⁺, and CD57⁺TIM3⁺ exhausted/senescent CD4 T cells at baseline independently predicted poor adaptive functional immune responses despite multiple boosters, regardless of SOT type and immunosuppressive regimen (area under the curve 0.89, 95% confidence interval 0.81-0.97, sensitivity 0.79, specificity 0.92). Such phenotypes were predominantly observed among tacrolimus/mycophenolate-based regimens. Moreover, SOT recipients with high percentages of CD57⁺, CD57⁺PD1⁺, and CD57⁺TIM3⁺ exhausted/senescent CD4 T cells at baseline predicted severe COVID-19 (area under the curve 0.88, P < .01). Our study adds preliminary new insight in the field and has clinical implications for risk-stratification against COVID-19 and other viral infections, ultimately guiding decision-making for establishing preventive strategies in SOT patients.